The development of optimal strategies to treat impaired mobility related to ageing and chronic disease requires better ways to detect and measure it. Digital health technology, including body worn ...sensors, has the potential to directly and accurately capture real-world mobility. Mobilise-D consists of 34 partners from 13 countries who are working together to jointly develop and implement a digital mobility assessment solution to demonstrate that real-world digital mobility outcomes have the potential to provide a better, safer, and quicker way to assess, monitor, and predict the efficacy of new interventions on impaired mobility. The overarching objective of the study is to establish the clinical validity of digital outcomes in patient populations impacted by mobility challenges, and to support engagement with regulatory and health technology agencies towards acceptance of digital mobility assessment in regulatory and health technology assessment decisions. The Mobilise-D clinical validation study is a longitudinal observational cohort study that will recruit 2400 participants from four clinical cohorts. The populations of the Innovative Medicine Initiative-Joint Undertaking represent neurodegenerative conditions (Parkinson's Disease), respiratory disease (Chronic Obstructive Pulmonary Disease), neuro-inflammatory disorder (Multiple Sclerosis), fall-related injuries, osteoporosis, sarcopenia, and frailty (Proximal Femoral Fracture). In total, 17 clinical sites in ten countries will recruit participants who will be evaluated every six months over a period of two years. A wide range of core and cohort specific outcome measures will be collected, spanning patient-reported, observer-reported, and clinician-reported outcomes as well as performance-based outcomes (physical measures and cognitive/mental measures). Daily-living mobility and physical capacity will be assessed directly using a wearable device. These four clinical cohorts were chosen to obtain generalizable clinical findings, including diverse clinical, cultural, geographical, and age representation. The disease cohorts include a broad and heterogeneous range of subject characteristics with varying chronic care needs, and represent different trajectories of mobility disability. The results of Mobilise-D will provide longitudinal data on the use of digital mobility outcomes to identify, stratify, and monitor disability. This will support the development of widespread, cost-effective access to optimal clinical mobility management through personalised healthcare. Further, Mobilise-D will provide evidence-based, direct measures which can be endorsed by regulatory agencies and health technology assessment bodies to quantify the impact of disease-modifying interventions on mobility.
IntroductionExisting mobility endpoints based on functional performance, physical assessments and patient self-reporting are often affected by lack of sensitivity, limiting their utility in clinical ...practice. Wearable devices including inertial measurement units (IMUs) can overcome these limitations by quantifying digital mobility outcomes (DMOs) both during supervised structured assessments and in real-world conditions. The validity of IMU-based methods in the real-world, however, is still limited in patient populations. Rigorous validation procedures should cover the device metrological verification, the validation of the algorithms for the DMOs computation specifically for the population of interest and in daily life situations, and the users’ perspective on the device.Methods and analysisThis protocol was designed to establish the technical validity and patient acceptability of the approach used to quantify digital mobility in the real world by Mobilise-D, a consortium funded by the European Union (EU) as part of the Innovative Medicine Initiative, aiming at fostering regulatory approval and clinical adoption of DMOs.After defining the procedures for the metrological verification of an IMU-based device, the experimental procedures for the validation of algorithms used to calculate the DMOs are presented. These include laboratory and real-world assessment in 120 participants from five groups: healthy older adults; chronic obstructive pulmonary disease, Parkinson’s disease, multiple sclerosis, proximal femoral fracture and congestive heart failure. DMOs extracted from the monitoring device will be compared with those from different reference systems, chosen according to the contexts of observation. Questionnaires and interviews will evaluate the users’ perspective on the deployed technology and relevance of the mobility assessment.Ethics and disseminationThe study has been granted ethics approval by the centre’s committees (London—Bloomsbury Research Ethics committee; Helsinki Committee, Tel Aviv Sourasky Medical Centre; Medical Faculties of The University of Tübingen and of the University of Kiel). Data and algorithms will be made publicly available.Trial registration numberISRCTN (12246987).
Although the value of patient and public involvement and engagement (PPIE) activities in the development of new interventions and tools is well known, little guidance exists on how to perform these ...activities in a meaningful way. This is particularly true within large research consortia that target multiple objectives, include multiple patient groups, and work across many countries. Without clear guidance, there is a risk that PPIE may not capture patient opinions and needs correctly, thereby reducing the usefulness and effectiveness of new tools. Mobilise-D is an example of a large research consortium that aims to develop new digital outcome measures for real-world walking in 4 patient cohorts. Mobility is an important indicator of physical health. As such, there is potential clinical value in being able to accurately measure a person's mobility in their daily life environment to help researchers and clinicians better track changes and patterns in a person's daily life and activities. To achieve this, there is a need to create new ways of measuring walking. Recent advancements in digital technology help researchers meet this need. However, before any new measure can be used, researchers, health care professionals, and regulators need to know that the digital method is accurate and both accepted by and produces meaningful outcomes for patients and clinicians. Therefore, this paper outlines how PPIE structures were developed in the Mobilise-D consortium, providing details about the steps taken to implement PPIE, the experiences PPIE contributors had within this process, the lessons learned from the experiences, and recommendations for others who may want to do similar work in the future. The work outlined in this paper provided the Mobilise-D consortium with a foundation from which future PPIE tasks can be created and managed with clearly defined collaboration between researchers and patient representatives across Europe. This paper provides guidance on the work required to set up PPIE structures within a large consortium to promote and support the creation of meaningful and efficient PPIE related to the development of digital mobility outcomes.
Measuring mobility in daily life entails dealing with confounding factors arising from multiple sources, including pathological characteristics, patient specific walking strategies, ...environment/context, and purpose of the task. The primary aim of this study is to propose and validate a protocol for simulating real-world gait accounting for all these factors within a single set of observations, while ensuring minimisation of participant burden and safety.
The protocol included eight motor tasks at varying speed, incline/steps, surface, path shape, cognitive demand, and included postures that may abruptly alter the participants' strategy of walking. It was deployed in a convenience sample of 108 participants recruited from six cohorts that included older healthy adults (HA) and participants with potentially altered mobility due to Parkinson's disease (PD), multiple sclerosis (MS), proximal femoral fracture (PFF), chronic obstructive pulmonary disease (COPD) or congestive heart failure (CHF). A novelty introduced in the protocol was the tiered approach to increase difficulty both within the same task (e.g., by allowing use of aids or armrests) and across tasks.
The protocol proved to be safe and feasible (all participants could complete it and no adverse events were recorded) and the addition of the more complex tasks allowed a much greater spread in walking speeds to be achieved compared to standard straight walking trials. Furthermore, it allowed a representation of a variety of daily life relevant mobility aspects and can therefore be used for the validation of monitoring devices used in real life.
The protocol allowed for measuring gait in a variety of pathological conditions suggests that it can also be used to detect changes in gait due to, for example, the onset or progression of a disease, or due to therapy.
ISRCTN-12246987.
Background
Rheumatoid arthritis is a major inflammatory disorder and causes substantial disability. Treatment goals span minimising disease activity, achieving remission and decreasing disability. In ...active rheumatoid arthritis, intensive management achieves these goals. As many patients with established rheumatoid arthritis have moderate disease activity, the TITRATE (Treatment Intensities and Targets in Rheumatoid Arthritis ThErapy) programme assessed the benefits of intensive management.
Objectives
To (1) define how to deliver intensive therapy in moderate established rheumatoid arthritis; (2) establish its clinical effectiveness and cost-effectiveness in a trial; and (3) evaluate evidence supporting intensive management in observational studies and completed trials.
Design
Observational studies, secondary analyses of completed trials and systematic reviews assessed existing evidence about intensive management. Qualitative research, patient workshops and systematic reviews defined how to deliver it. The trial assessed its clinical effectiveness and cost-effectiveness in moderate established rheumatoid arthritis.
Setting
Observational studies (in three London centres) involved 3167 patients. These were supplemented by secondary analyses of three previously completed trials (in centres across all English regions), involving 668 patients. Qualitative studies assessed expectations (nine patients in four London centres) and experiences of intensive management (15 patients in 10 centres across England). The main clinical trial enrolled 335 patients with diverse socioeconomic deprivation and ethnicity (in 39 centres across all English regions).
Participants
Patients with established moderately active rheumatoid arthritis receiving conventional disease-modifying drugs.
Interventions
Intensive management used combinations of conventional disease-modifying drugs, biologics (particularly tumour necrosis factor inhibitors) and depot steroid injections; nurses saw patients monthly, adjusted treatment and provided supportive person-centred psychoeducation. Control patients received standard care.
Main outcome measures
Disease Activity Score for 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR)-categorised patients (active to remission). Remission (DAS28-ESR < 2.60) was the treatment target. Other outcomes included fatigue (measured on a 100-mm visual analogue scale), disability (as measured on the Health Assessment Questionnaire), harms and resource use for economic assessments.
Results
Evaluation of existing evidence for intensive rheumatoid arthritis management showed the following. First, in observational studies, DAS28-ESR scores decreased over 10–20 years, whereas remissions and treatment intensities increased. Second, in systematic reviews of published trials, all intensive management strategies increased remissions. Finally, patients with high disability scores had fewer remissions. Qualitative studies of rheumatoid arthritis patients, workshops and systematic reviews helped develop an intensive management pathway. A 2-day training session for rheumatology practitioners explained its use, including motivational interviewing techniques and patient handbooks. The trial screened 459 patients and randomised 335 patients (168 patients received intensive management and 167 patients received standard care). A total of 303 patients provided 12-month outcome data. Intention-to-treat analysis showed intensive management increased DAS28-ESR 12-month remissions, compared with standard care (32% vs. 18%, odds ratio 2.17, 95% confidence interval 1.28 to 3.68;
p
= 0.004), and reduced fatigue mean difference –18, 95% confidence interval –24 to –11 (scale 0–100);
p
< 0.001. Disability (as measured on the Health Assessment Questionnaire) decreased when intensive management patients achieved remission (difference –0.40, 95% confidence interval –0.57 to –0.22) and these differences were considered clinically relevant. However, in all intensive management patients reductions in the Health Assessment Questionnaire scores were less marked (difference –0.1, 95% confidence interval –0.2 to 0.0). The numbers of serious adverse events (intensive management
n
= 15 vs. standard care
n
= 11) and other adverse events (intensive management
n
= 114 vs. standard care
n
= 151) were similar. Economic analysis showed that the base-case incremental cost-effectiveness ratio was £43,972 from NHS and Personal Social Services cost perspectives. The probability of meeting a willingness-to-pay threshold of £30,000 was 17%. The incremental cost-effectiveness ratio decreased to £29,363 after including patients’ personal costs and lost working time, corresponding to a 50% probability that intensive management is cost-effective at English willingness-to-pay thresholds. Analysing trial baseline predictors showed that remission predictors comprised baseline DAS28-ESR, disability scores and body mass index. A 6-month extension study (involving 95 intensive management patients) showed fewer remissions by 18 months, although more sustained remissions were more likley to persist. Qualitative research in trial completers showed that intensive management was acceptable and treatment support from specialist nurses was beneficial.
Limitations
The main limitations comprised (1) using single time point remissions rather than sustained responses, (2) uncertainty about benefits of different aspects of intensive management and differences in its delivery across centres, (3) doubts about optimal treatment of patients unresponsive to intensive management and (4) the lack of formal international definitions of ‘intensive management’.
Conclusion
The benefits of intensive management need to be set against its additional costs. These were relatively high. Not all patients benefited. Patients with high pretreatment physical disability or who were substantially overweight usually did not achieve remission.
Future work
Further research should (1) identify the most effective components of the intervention, (2) consider its most cost-effective delivery and (3) identify alternative strategies for patients not responding to intensive management.
Trial registration
Current Controlled Trials ISRCTN70160382.
Funding
This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in
Programme Grants for Applied Research
; Vol. 9, No. 8. See the NIHR Journals Library website for further project information.
Treat-to-target in rheumatoid arthritis (RA) recommends targeting remission, with low disease activity (LDA) being an alternative goal. When deciding to target remission or LDA, important ...considerations are the likelihood of attaining them, and their impacts on function and health-related quality of life (HRQoL). We have addressed this by studying: (a) the frequency of remission and LDA/remission; (b) DAS28-ESR trends after remission; (c) ability of remission vs. LDA to identify patients with normal function (HAQ ≤ 0.5) and HRQoL (EQ-5D ≥ the normal population).
We studied 571 patients in two clinical trials, and 1693 patients in a 10-year routine care cohort. We assessed the frequency and sustainability of remission and LDA/remission, variability in DAS28-ESR after remission, and sensitivity/specificity of remission and LDA/remission at identifying patients with low disability levels and normal HRQoL using Receiver Operator Characteristic (ROC) curves.
Point remission and remission/LDA were common (achieved by 35–58% and 49–74% of patients, respectively), but were rarely sustained (sustained remission and remission/LDA achieved by 5–9% and 9–16% of patients, respectively). Following attaining remission, DAS28-ESR levels varied substantially. Despite this, of those patients attaining point remission, the majority (53–61%) were in remission at study end-points. Whilst remission was highly specific at identifying patients with low disability (85–91%) it lacked sensitivity (51–57%); similar findings were seen for normal HRQoL (specificity 78–86%; sensitivity 52–59%). The optimal DAS28-cut-off to identify individuals with low disability and normal HRQoL was around the LDA threshold.
Our findings support both the treat-to-target goals. Attaining remission is highly specific for attaining low disability and normal HRQoL, although many patients with more active disease also have good function and HRQoL. Attaining a DAS28-ESR ≤ 3.2 has a better balance of specificity and sensitivity for attaining these outcomes, with the benefit of being more readily achievable. Although sustaining these targets over time is rare, even attaining them on a one-off basis leads to better function and HRQoL outcomes for patients.
Many trials have shown that intensive management is effective in patients with early active rheumatoid arthritis (RA). But its benefits are unproven for the large number of RA patients seen in ...routine care who have established, moderately active RA and are already taking conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs). The TITRATE trial studied whether these patients also benefit from intensive management and, in particular, achieve more remissions.
A 12-month multicentre individually randomised trial compared standard care with monthly intensive management appointments which was delivered by specially trained healthcare professionals and incorporated monthly clinical assessments, medication titration and psychosocial support. The primary outcome was 12-month remission assessed using the Disease Activity Score for 28 joints using ESR (DAS28-ESR). Secondary outcomes included fatigue, disability, harms and healthcare costs. Intention-to-treat multivariable logistic- and linear regression analyses compared treatment arms with multiple imputation used for missing data.
459 patients were screened and 335 were randomised (168 intensive management; 167 standard care); 303 (90%) patients provided 12-month outcomes. Intensive management increased DAS28-ESR 12-month remissions compared to standard care (32% vs 18%, p = 0.004). Intensive management also significantly increased remissions using a range of alternative remission criteria and increased patients with DAS28-ESR low disease activity scores. (48% vs 32%, p = 0.005). In addition it substantially reduced fatigue (mean difference -18; 95% CI: -24, -11, p<0.001). There was no evidence that serious adverse events (intensive management =15 vs standard care =11) or other adverse events (114 vs 151) significantly increase with intensive management.
The trial shows that intensive management incorporating psychosocial support delivered by specially trained healthcare professions is effective in moderately active established RA. More patients achieve remissions, there were greater improvements in fatigue, and there were no more harms.
We systematically reviewed the effectiveness of intensive treatment strategies in achieving remission in patients with both early and established Rheumatoid Arthritis (RA).
A systematic literature ...review and meta-analysis evaluated trials and comparative studies reporting remission in RA patients treated intensively with disease modifying anti-rheumatic drugs (DMARDs), biologics and Janus Kinase (JAK) inhibitors. Analysis used RevMan 5.3 to report relative risks (RR) in random effects models with 95% confidence intervals (CI).
We identified 928 publications: 53 studies were included (48 superiority studies; 6 head-to-head trials). In the superiority studies 3013/11259 patients achieved remission with intensive treatment compared with 1211/8493 of controls. Analysis of the 53 comparisons showed a significant benefit for intensive treatment (RR 2.23; 95% CI 1.90, 2.61). Intensive treatment increased remissions in both early RA (23 comparisons; RR 1.56; 1.38, 1.76) and established RA (29 comparisons RR 4.21, 2.92, 6.07). All intensive strategies (combination DMARDs, biologics, JAK inhibitors) increased remissions. In the 6 head-to-head trials 317/787 patients achieved remission with biologics compared with 229/671 of patients receiving combination DMARD therapies and there was no difference between treatment strategies (RR 1.06; 0.93. 1.21). There were differences in the frequency of remissions between early and established RA. In early RA the frequency of remissions with active treatment was 49% compared with 34% in controls. In established RA the frequency of remissions with active treatment was 19% compared with 6% in controls.
Intensive treatment with combination DMARDs, biologics or JAK inhibitors increases the frequency of remission compared to control non-intensive strategies. The benefits are seen in both early and established RA.
Uncontrolled active rheumatoid arthritis can lead to increasing disability and reduced quality of life over time. 'Treating to target' has been shown to be effective in active established disease and ...also in early disease. However, there is a lack of nationally agreed treatment protocols for patients with established rheumatoid arthritis who have intermediate disease activity. This trial is designed to investigate whether intensive management of disease leads to a greater number of remissions at 12 months. Levels of disability and quality of life, and acceptability and cost-effectiveness of the intervention will also be examined.
The trial is a 12-month, pragmatic, randomised, open-label, two-arm, parallel-group, multicentre trial undertaken at specialist rheumatology centres across England. Three hundred and ninety-eight patients with established rheumatoid arthritis will be recruited. They will currently have intermediate disease activity (disease activity score for 28 joints assessed using an erythrocyte sedimentation rate of 3.2 to 5.1 with at least three active joints) and will be taking at least one disease-modifying anti-rheumatic drug. Participants will be randomly selected to receive intensive management or standard care. Intensive management will involve monthly clinical reviews with a specialist health practitioner, where drug treatment will be optimised and an individualised treatment support programme delivered based on several principles of motivational interviewing to address identified problem areas, such as pain, fatigue and adherence. Standard care will follow standard local pathways and will be in line with current English guidelines from the National Institute for Health and Clinical Excellence. Patients will be assessed initially and at 6 and 12 months through self-completed questionnaires and clinical evaluation.
The trial will establish whether the known benefits of intensive treatment strategies in active rheumatoid arthritis are also seen in patients with established rheumatoid arthritis who have moderately active disease. It will evaluate both the clinical and cost-effectiveness of intensive treatment.
Current Controlled Trials, ID: ISRCTN70160382 . Registered on 16 January 2014.
BackgroundThe development of optimal strategies to treat impaired mobility related to ageing and chronic disease requires better ways to detect and measure it. Digital health technology, including ...body worn sensors, has the potential to directly and accurately capture real-world mobility. Mobilise-D consists of 34 partners from 13 countries who are working together to jointly develop and implement a digital mobility assessment solution to demonstrate that real-world digital mobility outcomes have the potential to provide a better, safer, and quicker way to assess, monitor, and predict the efficacy of new interventions on impaired mobility. The overarching objective of the study is to establish the clinical validity of digital outcomes in patient populations impacted by mobility challenges, and to support engagement with regulatory and health technology agencies towards acceptance of digital mobility assessment in regulatory and health technology assessment decisions.Methods/designThe Mobilise-D clinical validation study is a longitudinal observational cohort study that will recruit 2400 participants from four clinical cohorts. The populations of the Innovative Medicine Initiative-Joint Undertaking represent neurodegenerative conditions (Parkinson's Disease), respiratory disease (Chronic Obstructive Pulmonary Disease), neuro-inflammatory disorder (Multiple Sclerosis), fall-related injuries, osteoporosis, sarcopenia, and frailty (Proximal Femoral Fracture). In total, 17 clinical sites in ten countries will recruit participants who will be evaluated every six months over a period of two years. A wide range of core and cohort specific outcome measures will be collected, spanning patient-reported, observer-reported, and clinician-reported outcomes as well as performance-based outcomes (physical measures and cognitive/mental measures). Daily-living mobility and physical capacity will be assessed directly using a wearable device. These four clinical cohorts were chosen to obtain generalizable clinical findings, including diverse clinical, cultural, geographical, and age representation. The disease cohorts include a broad and heterogeneous range of subject characteristics with varying chronic care needs, and represent different trajectories of mobility disability.DiscussionThe results of Mobilise-D will provide longitudinal data on the use of digital mobility outcomes to identify, stratify, and monitor disability. This will support the development of widespread, cost-effective access to optimal clinical mobility management through personalised healthcare. Further, Mobilise-D will provide evidence-based, direct measures which can be endorsed by regulatory agencies and health technology assessment bodies to quantify the impact of disease-modifying interventions on mobility.Trial registrationISRCTN12051706.
PDF
